The NIH established the Molecular Libraries Program (MLP) and its network of high-throughput screening (HTS) centers to discover probes ? highly selective small molecules that modulate cellular function ? within the proteomes of humans and pathogens. Probes are not only tools for studying biological function to validate new drug targets, but are also potential leads for new therapeutics. Though successful in its mission to provide HTS resources to academia and having generated hundreds of probes, the MLP is sunsetting and its operational screening centers face the logistic and financial issues that industrial HTS centers have battled for decades (large facilities, costly robotic handling and optical screening equipment upkeep, static compound libraries). Proteome-wide and pathogen-wide probe discovery remains a compelling goal well within reach thanks to distributed and economical genome sequencing technology, which inspires this proposal to develop a similarly distributable molecular screening platform. Combining droplet-scale microfluidic miniaturization and automation with consumable DNA-encoded solid-phase compound libraries comprises a proposed bid to reconstitute the operations of a HTS center in a single benchtop instrument. The device loads compound library beads into picoliter-scale droplets of assay reagent, photochemically cleaves the compound from the bead, incubates the dosed droplets, reads the fluorescence of the incubated droplets, and sorts droplets exhibiting a desired assay fluorescence profile for collection and high-throughput sequencing. The instrument will (1) screen a million compound library in ~6 h, (2) require several square feet of space, (3) consume ~100 L of assay reagent, and (4) generate dose-response screening data, resulting in massively parallel pan-library structure-activity relationship profiles. This technology will distribute molecular screening, moving it into academic, industrial and government laboratories nationwide, and on a cost scale that will enable discovery of thousands of probes annually.